Alzheimer's disease is a dementing disorder affecting over one million Americans. Morphologically it is characterized by numerous neurofibrillary tangles and senile plaques primarily in the cerebral cortex. Autopsied brain tissue from patients with Alzheimer's disease shows levels of choline acetyltransferase and acetylcholinesterase reduced to 10 to 30% of that of age-matched controls. Levels of several other neurotransmitters and enzymes are normal, suggesting a selective degeneration of cholinergic neurons and therefore a specific mechanism for the disease. Aims and Long Term Objectives--This proposal aims to test whether chronic inhibition of brain choline acetyltransferase in rabbits will produce the plaques and neurofibrillary tangles associated with the disease in humans. If so, then a defect in the production or regulation of this enzyme may be the cause of the human disease. In addition a convenient animal model for the disease would be in hand. If choline acetyltransferase inhibition does not induce the morphology of Alzheimer's disease then the reduction of this enzyme in the human disease may not be the cause of the disease but may be the result of an underlying process. Thus the long term objectives of this proposal are to determine whether reduced choline acetyltransferase is a cause of Alzheimer's disease and to produce an animal model for this degenerative process. Methodology--We propose to treat rabbits chronically (weeks to months) with the choline acetyl transferase inhibitor acetylsecohemicholinium-3 and to examine the cerebral cortex for the plaques and tangles found in Alzheimer's disease. Acetylsecohemicholinium-3 reduces acetyl choline levels when given intraventricularly to rats. However neurofibrillary tangles have been produced in rabbits by injection of aluminum salts and thus rabbits may be the best model for neurofibrillary degeneration. The inhibitor will be administered to normal and aluminum treated rabbits both intraventricularly and directly into the nucleus basalis, thought to be the source of choline acetyltransferase for the cerebral cortex. This project involves neurochemistry and experimental pathology and is a change of field of research for the principal investigator.